Locked-in syndrome is a rare neuropsychological disorder. Its primary features are quadriplegia and paralysis of the cranial nerves except for those responsible for vertical eye movements. The differential diagnosis includes persistent vegetative state, brain death, minimally conscious states, C3 transection of the spinal cord, and conversion locked-in syndrome. Etiologies of locked-in syndrome include hemorrhagic and thrombotic events, tumors affecting the ventral pons, infectious agents, iatrogenic causes, trauma, metabolic abnormalities, and other miscellaneous causes. The clinical manifestations, differential diagnosis, neuropsychological assessment, rehabilitation, and prognosis of patients with locked-in syndrome are discussed.

Introduction

Imagine wakening from a deep sleep to find yourself fully conscious but unable to move any voluntary muscles save for the muscles that control your vertical eye movements. You can see, hear, smell, taste, and even feel the bed sheets against your skin. However, you are unable to speak or make any vocalizations at all. You are totally disconnected from your external world in a real sense. You may appear to be in a coma to others although you are quite capable of understanding their speech and actions. You are, in essence, locked in your own body. This scenario is not a fantasy that Rod Sterling would have written for a Twilight Zone episode but a recognized, though rare, neuropsychological syndrome.

Locked-in syndrome was first described in the modern era by Cairns and associates in 1941.1 A 15-year-old girl had an epidermoid tumor of the third ventricle that resulted in a state of akinetic mutism; she could move her eyes but was unable to move any other muscle group voluntarily. The authors theorized that pressure placed on the surrounding neural structures by the epidermoid cyst created a disconnection between the diencephalon and the cerebral cortex. Fortunately, after needle aspiration of the cyst, the girl's neurological functions recovered.

The earliest recorded description of locked-in syndrome comes from Alexandre Dumas's novel, The Count of Monte Cristo.2 Monsignor Noirtier de Villefort, stricken with cardiovascular disease, was unable to move voluntarily or to speak but was able to move his eyes. With the assistance of his associate, the Monsignor could communicate by blinking his eyes when his associate pointed to words in a dictionary.

The most recently publicized case of locked-in syndrome is that of Jean-Dominique Bauby, the late editor-in-chief of the French magazine Elle.3 Bauby suffered a massive stroke of his brain stem at age 43 years that left him with locked-in syndrome. He was able to communicate by using a system very similar to that used by Monsignor Noirtier de Villefort. The alphabet was written on a large board in Bauby's hospital room and ordered to frequency of occurrence in the French language: ESARINTULOMDPCFBVHGJQZYXKW. A family member or friend would point to a letter, starting at the beginning with the letter E. Bauby would blink when the letter was correct and thus was able to form words and then sentences.4 While this may seem very elementary, what is amazing and is a testament to human will power and perseverance is that Bauby was able to memorialize his experience in the locked-in state by writing The Diving Bell and the Butterfly prior to his untimely death.5 The locked-in syndrome became Bauby's diving bell that held his body prisoner. However, his mind, like a butterfly, was able to take flight. Bauby died in 1997, two days after his book was published.

Clinical Manifestations of Locked-In Syndrome

Locked-in syndrome has been referred to as akinetic mutism because of its clinical manifestations. Other terms that have been used interchangeably with locked-in syndrome include cerebromedullospinal dissociation, de-efferented state, pseudocoma, coma vigilante, and locked-in state.6,7 Most of these descriptive appellations are attempts at identifying the key clinical features of the syndrome. The signs and symptoms of locked-in syndrome become apparent after the patient awakens gradually from a coma caused by the inciting event.8 While comatose, the patient usually requires ventilator assistance. The patient is quadriplegic and has cranial nerve involvement resulting in lateral gaze palsy and paralytic mutism.9 However, vertical eye movement and blinking are usually intact. The patient is fully conscious unless the brain has received extensive injury from the inciting event.

The brain injury that results in locked-in syndrome is a lesion to the ventral pons from hemorrhage, trauma, and other etiologies that will be discussed below.10 The pontine lesion interrupts the corticospinal tract and produces quadriplegia.9 The injury to the corticobulbar tract especially affects cranial nerves XI and XII, the accessory and hypoglossal nerves. These cranial nerves are essential for control of the facial, pharyngeal, and tongue muscles that are involved in speech and vocalization. The paralysis of these muscle groups causes anarthria or akinetic mutism. The preservation of the supranuclear motor pathways allows the patient with locked-in syndrome to open his or her eyes, blink, and produce vertical eye movements. However, other eye movements may be adversely affected due to selective anatomical lesioning of the pons including the paramedian pontine reticular formation or abducens nucleus.9

Although a ventral pontine lesion is the etiology of locked-in syndrome, not all patients with this lesion will have an identical clinical presentation. Locked-in syndrome has been classified into three categories according to clinical presentation: classic locked-in syndrome, incomplete locked-in syndrome, and total locked-in syndrome.10 In the classic case of locked-in syndrome, the patient has quadriplegia and anarthria but is conscious and has vertical eye movements. The patient with incomplete locked-in syndrome has the same features as the patient with classic locked-in syndrome but may have very limited voluntary movement of muscle groups such as facial muscles or the upper extremity muscle groups. A patient with total locked-in syndrome is totally paralyzed and conscious; no eye movements are possible and, therefore, the patient is essentially incommunicative. These categories have also been subcategorized into transient and chronic types.10

Until recently, locked-in syndrome has been viewed mostly from the neuroanatomical perspective with very little clinical investigation into the cognitive impairments of patients with the syndrome. Most of these patients in the past, like Jean-Dominique Bauby, succumbed to their underlying disease or complications thereof in a year or two after the onset of locked-in syndrome. However, with the assistance of recent medical technological advances, these patients may live for a considerable period of time. The 5-, 10-, and 20-year survival rates are 83%, 83%, and 40% respectively.11 Like Bauby and the Monsignor, most of the patients with locked-in syndrome are able to communicate by using blinking and other eye movements, thereby making it possible to determine whether cognitive impairments may accompany their locked-in syndrome.

New and Thomas reported significant cognitive impairments in a case study of a man aged 30 years with classic locked-in syndrome due to occlusion of the basilar artery.12 Although the patient gradually recovered partial neurological function over a 2-year period, he had permanent attention deficits, prolonged processing speed, disorganization of perceptual skills, difficulty in learning new verbal information, and executive dysfunction. The researchers also noted pathologic laughing and crying. Leon-Carrion and associates in a review of 44 patients with locked-in syndrome reported that 8 patients had significant memory problems while 6 had serious attentional deficits.9

Psychotic symptoms have also been reported in a patient with locked-in syndrome.13 The patient had hemorrhage into the pons and mesencephalon. During rehabilitation, the patient manifested psychotic symptoms and required an antipsychotic to control the symptoms. The patient had no preexisting history of mental disorders.

Differential Diagnosis of Locked-In Syndrome

Because of the rarity of locked-in syndrome, most clinicians might encounter such a patient once or twice during their careers. In a review of all patients with locked-in syndrome admitted to the Finnish national rehabilitation center, Kapyla Rehabilitation Centre, between 1979 and 2000, only 17 cases were found.2 The rarity of the syndrome and the overlapping features of locked-in syndrome with other neurological syndromes frequently lead to a misdiagnosis or delayed diagnosis. The average time required for diagnosis of locked-in syndrome is 2.5 months, and in some cases, the definitive diagnosis is not established until 4 to 6 years after presentation.8

The differential diagnosis of locked-in syndrome includes high tetraplegia caused by a spinal cord lesion at C3, persistent vegetative state, brain death, and minimally conscious states.14,15 When advanced radiological techniques such as computed tomography (CT) scans and magnetic resonance imaging (MRI) and electrophysiological testing (eg, electroencephalography [EEG]) were not available, the health care provider had only clinical skills to aid in arriving at a correct diagnosis. It is quite easy to see why a case of total locked-in syndrome might be confused with brain death or with these other neurological conditions.

A patient with high tetraplegia caused by a spinal cord lesion at C3 is unable to move any muscle groups save those innervated by the cranial nerves. Therefore, the patient is usually able to communicate verbally. For the most part, the diagnosis is rather clear.14

Differentiation of the persistent vegetative state from locked-in syndrome is more problematic. The definition of the persistent vegetative state depends upon the domain of interest: anatomical, behavioral, or state of consciousness.16 From the anatomical perspective, the persistent vegetative state is the result of destruction of the entire cerebral cortex with sparing of the brain stem. This state has also been referred to as neocortical death. The persistent vegetative state as defined by the behavioral domain is clinically determined and is a state of eyes-open unresponsiveness. Finally, the state of consciousness domain predisposes a patient's perspective of consciousness: the patient is unaware of self and surroundings. In an attempt to clarify the meaning of the persistent vegetative state, the American Academy of Neurology issued an opinion that the persistent vegetative state is a permanent state of unconsciousness due to lack of cortical functioning.17 However, the academy's opinion has been criticized for its circular reasoning approach.16

The use of electrophysiological testing, functional MRI (fMRI), and positron emission tomography (PET) scans has enabled clinicians nowadays to readily differentiate the persistent vegetative state from locked-in syndrome, even in patients with total locked-in syndrome.15 However, if these modalities are not available, it may still be difficult initially to differentiate patients with brain death from patients with minimally conscious states or locked-in syndrome. Even after testing, some cases of minimally conscious state cannot be differentiated from locked-in syndrome.

Patients with minimally conscious states have discrete, yet fleeting, episodes of behavioral evidence of consciousness.18 These episodes are sporadic and cannot be elicited. There may be eye movement similar to that seen in locked-in syndrome. Neuroradiological studies may fail to detect any lesions. Continuing observation and evaluation are needed to differentiate the two conditions, if at all possible.

Finally, the clinician must beware of conversion locked-in syndrome. Han and associates reported the case of a woman aged 42 years who manifested symptoms of locked-in syndrome after implantation of a spinal cord stimulator for chronic back pain.19 Over the several hours after initial presentation, the patient became asymptomatic. Psychological evaluation established the criteria for a conversion disorder that explained her condition.

Etiologies of Locked-In Syndrome

Most cases of locked-in syndrome reported in the literature are single case reports. Many causes of ventral pontine injury may result in locked-in syndrome. The most common etiologies include hemorrhage, thrombosis, trauma, infections, and aneurysms or dissections of the basilar or vertebral arteries.9,10 While most causes of locked-in syndrome result from pathophysiological processes such as tumors or infections, some cases are caused by iatrogenic influences. Iatrogenic causes include chiropractic spinal and head manipulations, use of drugs with thrombogenic properties, and regional anesthetic nerve blocks.20-22

The most common cause of locked-in syndrome is a hemorrhage or thrombosis of the basilar artery supplying the ventral pons.9 Hemorrhage or thrombosis of the basilar artery results in the basilar artery syndrome. Five types of basilar artery syndrome depend upon the extent of tissue damage and clinical symptoms. Type 1 basilar artery syndrome involves total infarction of the watershed area of the basilar area and results in immediate death. Type 5 basilar artery syndrome has negative CT findings of infarction but positive angiographic signs; clinical symptoms are minimal. Type 2 basilar artery syndrome may result in locked-in syndrome. There is extensive brain stem infarction and, if limited to the ventral pons, locked-in syndrome occurs.

Although most cases of locked-in syndrome caused by hemorrhage or thrombosis of the basilar artery occur in older persons with preexisting morbidities such as cardiovascular or cerebrovascular disease, younger people and even children may be victims of locked-in syndrome when the basilar or vertebral arteries are injured. In a review of 40 cases of basilar or vertebral artery occlusion in children aged from 6 to 14 years, 10 children had locked-in syndrome.23 The basilar or vertebral occlusion was caused by thrombosis, hemorrhage, and other assorted causes.

Hemorrhagic injury to the ventral pons may also be caused by dissection of the basilar or vertebral arteries from trauma. A boy aged 8 years who suffered a traumatic vertebral artery dissection was diagnosed with locked-in syndrome after a brief loss of consciousness.24 The ischemic stroke caused by the vertebral artery dissection was treated with a course of anticoagulants. After 10 days of therapy, the boy recovered fully.

Trauma, as noted above, is often the inciting event that causes locked-in syndrome. The traumatic event will either cause a partial or complete occlusion of the vertebral or basilar arteries or a thrombosis or hemorrhage of the same arteries. The end result is infarction of the ventral pons. Fitzgerald, Simpson, and Trask reported a case of locked-in syndrome after a gunshot wound to the cervical spine.25 Both vertebral arteries were damaged by penetrating gunshot trauma. Eight hours after the injury, the basilar artery thrombosed. The authors opined that ascending thrombosis from the injured vertebral arteries caused thrombosis of the basilar artery leading to locked-in syndrome.

Tumors located strategically in the area of the ventral pons may cause locked-in syndrome from a variety of mechanisms. The case reported by Cairns and associates in the introduction illustrates the mass-effect mechanism by which a tumor may cause locked-in syndrome.1 Drainage of the tumor eliminated the mass-effect and alleviated the locked-in syndrome.

Brain stem tumors may also cause central pontine myelinolysis. Damage to the nerve tracts coursing through the ventral pons from myelinolysis is thought to be the mechanism responsible for locked-in syndrome in these cases. A case of locked-in syndrome caused by a slow-growing cerebellar astrocytoma leading to central pontine myelinolysis has been reported.26

Tumors may also invade the ventral pons and directly disrupt the coursing nerve tracts. In a series of 8 children with the terminal phase of pontine glioma, all developed locked-in syndrome days to months before death.27 The authors questioned whether ethically these children should have been kept on ventilator support until death as they were conscious yet terminal. Metastatic tumors to the ventral pons are also responsible for causing locked-in syndrome. A woman aged 31 years who had a right upper lobectomy for suspected metastatic cancer to the lungs was found to have locked-in syndrome after recovery from anesthesia.28 Seven months after surgery, she succumbed; autopsy revealed extensive infiltration of the ventral pons with tumor.

Various infectious agents have been cited as the cause of locked-in syndrome; these include pneumococcal bacteria and the Epstein-Barr virus.29,30 The mechanism leading to locked-in syndrome for pneumococcal meningitis was thought to be an infarction of the pons from direct invasion by bacteria. In the case of Epstein-Barr virus infection, inflammation of the ventral pons caused by the virus was the suggested mechanism.

Most cases of locked-in syndrome are due to pathophysiological processes as noted above. However, more than several cases of iatrogenic locked-in syndrome have been reported in the literature. Krieger, Leibold, and Bruckman reported the onset of locked-in syndrome in a woman aged 37 years after chiropractic manipulation of the cervical spine for pain in the neck and occipital areas.20 Digital subtraction angiography showed complete obstruction of the right vertebral artery. The left vertebral artery had a slight dissection. The patient was treated with anticoagulants and after 3 days, full neurological function returned.

Several cases of transient locked-in syndrome have been reported after regional anesthesia blocks. Regional nerve blocks of the intrascalene brachial plexus and the stellate ganglion have been identified as being responsible.21,22 In both cases, it was hypothesized that inadvertent injection of the anesthetic agent in the vertebral artery either depolarized the nerves coursing through the ventral pons or resulted in a temporary vasospasm of the vertebral and basilar arteries that led to a transient ischemia of the ventral pons. Both patients had a full recovery of neurological function.

Intrathecal injections of chemotherapeutic agents have also been implicated as a cause of locked-in syndrome.31 A man aged 22 years with malignant immunoblastic lymphoma received intrathecal cytosine arabinoside for tumor invasion of the spinal cord. Eight hours later, the patient experienced signs of locked-in syndrome that persisted until his death 3 weeks later. The authors posited a toxic idiosyncratic response to the chemotherapy as the cause of the patient's locked-in syndrome.

Rheumatologic disorders have been suspected as causes of locked-in syndrome.32 With these disorders, inflammation is widespread due to the autoimmune nature of the underlying disease. Vasculitis is very common. A young man with fibromuscular dysplasia presented with locked-in syndrome after an acute onset of stroke. Not long after, he died; an autopsy confirmed an infarction of the ventral pons and fibromuscular dysplasia of the basilar artery.

Metabolic abnormalities may also cause locked-in syndrome. A man aged 67 years with type 2 diabetes mellitus presented with locked-in syndrome after sustaining an episode of hypoglycemia.33 Once treated with intravenous glucose, his locked-in syndrome resolved promptly. Rapid correction of hyponatremia may cause locked-in syndrome.34 A girl aged 15 years developed locked-in syndrome after rapid correction of hyponatremia. Pontine myelinolysis resulted from the rapid correction of hyponatremia. The girl did not recover and died several days later. The authors warned that rapid correction of hyponatremia should be avoided at all costs to prevent similar tragic outcomes.

Neuropsychological Assessment of Locked-In Syndrome

The typical patient with locked-in syndrome presents after a catastrophic event that placed the patient in an altered state of consciousness for a period of time.10 Most patients will have been in a comatose state for days to months and then will gradually emerge from consciousness.8 These historical findings are important in suspecting the clinical diagnosis of locked-in syndrome. The standard neurological examination is necessary in determining the overall neurological status of the patient.15

After reviewing the history and performance of the standard neurological examination, the clinician must determine whether further assessment is needed. The patient may have been initially evaluated by CT scans or MRI to determine the nature of brain injury. Some patients may have had angiographic examinations to determine whether thrombosis, dissection, or aneurysms of the basilar or vertebral arteries have occurred.9 Repeating these studies once the patient has awakened from the comatose state may be necessary.

Further neuropsychological assessment is needed if the diagnosis of locked-in syndrome is not clear. Patients with extensive lesions of the ventral pons may have total locked-in syndrome; eye movements are limited. Electrophysiological testing is necessary in ruling out brain death.35 Electroencephalography and evoked potential testing are valuable diagnostic tests in differentiating brain stem lesions (normal-appearing EEG) from brain death (flat EEG) or psychogenic unresponsiveness (normal EEG with alpha blocking and/or normal sleep-wake cycling).

Functional neuroradiological imaging may also be useful in evaluating the patient with suspected locked-in syndrome.35 These studies are particularly useful in narrowing the differential diagnosis and for prognostication. Invasive testing such as angiography may prove unnecessary if adequate information is obtained through fMRI or PET scanning.

Rehabilitation and Prognosis of Locked-In Syndrome

Most patients with locked-in syndrome will live 5 years or longer. These patients are conscious and most are able to communicate by eye movements. In a study by Doble and associates of a cohort of 29 patients with locked-in syndrome, 8 patients lived with their families and10 patients had not been hospitalized in the preceding year.11 Seven of the patients were satisfied with their lives, and 5 had occasional depression. Only one patient expressed an interest in dying. The authors concluded that after initial stabilization, patients with locked-in syndrome can have prolonged survival and are able to live outside of institutions if adequate support is provided.

The rehabilitation of the patient with locked-in syndrome is directed toward developing effective communication skills. For patients with the classic locked-in syndrome, the use of the ordered alphabet chart and eye blinking is the primary mode of communication. A more sophisticated, yet simpler version of the ordered alphabet chart has been developed for use specifically for patients with locked-in syndrome -- the AEIOU alphabet board.10 The letters are still ordered in frequency but are placed in color-coded rows on the chart. The assistant calls out a color and the patient will blink if correct; then the assistant calls out letters in the selected colored row. This is a timesaving device.

For patients with incomplete locked-in syndrome, voluntary movement of muscle groups other than the eye muscles is possible.3 These patients may use these other muscle groups to communicate. For example, the ability to move a digit or even the forehead may allow the patient to activate a device such as a laser to point to an interactive computer screen. The patient may then be able to use email, write letters, and use voice simulators to communicate. Two communications systems using infrared technology, Quick Glance and Eyegaze, are available for use by patients with incomplete locked-in syndrome.

Smith and Delargy reported that two patients with locked-in syndrome were able to return to work.10 One patient was an attorney with classic locked-in syndrome who used Morse code to give his legal opinions. The other patient was a teacher with incomplete locked-in syndrome who used a mouth stick to activate an electronic voice simulator. Another remarkable story involving a patient with locked-in syndrome is that of Judy Mozersky.3 Mozersky, a student at Cornell University, suffered a massive brain stem stroke that left her with classic locked-in syndrome before her junior year. With computer-assisted devices, she was able to complete her studies and to write her memoir, Locked In: A Young Woman's Battle With Stroke.

Recent developments in brain-computer communications may herald a new era in the rehabilitation of the patient with locked-in syndrome. Kubler and associates predicted in 2001 that brain-computer interfacing might enable the patient with classic locked-in syndrome to communicate beyond the AEIOU alphabet board and perhaps to gain mobility by using motorized wheelchair devices similar to those used by patients with quadriplegia.36 A few years later, they were able to establish a brain-computer interface, and the device was first used successfully in a boy aged 14 years with classic locked-in syndrome caused by amyotrophic lateral sclerosis.37

Conclusion

Locked-in syndrome is a rare neuropsychological syndrome; however, clinicians may encounter 1 to 2 cases during their careers. The syndrome's main features are quadriplegia and paralysis of the cranial nerves except for those responsible for vertical eye movements. The etiology of the syndrome is injury to the ventral pons from hemorrhage, thrombosis, trauma, infection, tumors, and other agents. The diagnosis may be difficult, but clinical suspicion supplemented by neuroimaging and electrophysiological studies will ascertain the correct diagnosis in most cases. Rehabilitation is directed toward establishing the patient's communicative skills. For most patients, a satisfactory life after injury can be attained. Future developments including brain-computer interfacing may enable patients with locked-in syndrome to become mobile and to communicate more easily, and may allow some patients to return to their former occupations.